Regiospecific Aza-Michael Addition of 4-Aryl-1H-1,2,3-triazoles to Chalcones: Synthesis of 2,4-Disubstituted 1,2,3-Triazoles in Basic Medium

Abstract

A novel metal-free and base-mediated method to display the donor ability of 1,2,3-triazoles for the synthesis of 2,4-disubstituted 1,2,3-triazoles has been developed. A DABCO-promoted aza-Michael addition of 4-aryl NH-1,2,3-triazoles to α,β-unsaturated ketones (chalcones) is presented. The reactions proceeded with complete regiospecificity in a 3:1 mixture of acetonitrile and methanol at 85 °C to provide 2,4-disubstituted 1,2,3-triazoles as Michael adducts, and the addition products 1,3-diaryl-(4-aryl-2H-1,2,3-triazol-2-yl)propan-1-ones were isolated in high yields.

Key words

triazoles - chalcones - aza-Michael addition - heterocyclic compounds

• References and Notes

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• 23 2,4-Disubstituted 1,2,3-Triazoles 3a–y; General ProcedureDABCO (0.2 mmol) was added to a mixture of the appropriate chalcone 1 (0.2 mmol) and 4-aryl-1H-1,2,3-triazole 2 (0.2 mmol) in 3:1 MeCN–MeOH (2 mL) in a 10 mL round-bottomed flask, and the mixture was stirred at 85 °C for 3 d until almost all the reactants were converted (TLC). The product was isolated by subjecting the crude reaction mixture to column chromatography (silica gel, 10–50% EtOAc–hexanes).
• 24 Experimental Data for Selected Compounds 3-[4-(2-Chlorophenyl)-2H-1,2,3-triazol-2-yl]-1-(4-methoxyphenyl)-3-(4-tolyl)propan-1-one (3a)Pale-yellow solid; yield: 57.0 mg (66%); mp 117.5–119.0 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.12 (s, 1 H), 7.99 (d, J = 8.8 Hz, 2 H), 7.82 (dd, J = 2.4, 7.2 Hz, 1 H), 7.42 (dd, J = 2.0, 7.2 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.29–7.22 (m, 2 H), 7.16 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 8.8 Hz, 2 H), 6.51 (dd, J = 8.8, 5.6 Hz, 1 H), 4.49 (dd, J = 8.8, 17.6 Hz, 1 H), 3.86 (s, OCH ₃, 3 H), 3.71 (dd, J = 5.6, 17.6 Hz, 1 H), 2.32 (s, CH ₃, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.3 (CO), 163.7 (C), 144.6 (C), 138.0 (C), 136.4 (C), 134.1 (CH), 131.9 (C), 130.5 (2CH), 130.3 (CH), 130.2 (CH), 129.4 (2CH), 129.4 (C), 129.2 (C), 129.1 (CH), 126.8 (CH), 126.6 (2CH), 113.7 (2CH), 64.2 (CH), 55.4 (OCH₃), 43.6 (CH₂), 21.1 (CH₃).1-(4-Methoxyphenyl)-3-[4-(4-methoxyphenyl)-2H-1,2,3-triazol-2-yl]-3-(2-tolyl)propan-1-one (3b)Pale-yellow solid; yield: 55.6 mg (65%); mp 114.0–115.5 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.00 (d, J = 8.8 Hz, 2 H), 7.74 (s, 1 H), 7.65 (d, J = 8.8 Hz, 2 H), 7.21–7.12 (m, 4 H), 6.94 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2 H), 6.75 (dd, J = 4.8, 9.2 Hz, 1 H), 4.49 (dd, J = 9.2, 17.6 Hz, 1 H), 3.86 (s, OCH ₃, 3 H), 3.82 (s, OCH ₃, 3 H), 3.57 (dd, J = 4.4, 17.6 Hz, 1 H), 2.57 (s, CH ₃, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.6 (CO), 163.7 (C), 159.6 (C), 147.3 (C), 137.9 (C), 135.2 (C), 130.8 (CH), 130.5 (2CH), 130.3 (CH), 129.5 (C), 128.0 (CH), 127.2 (2CH), 126.4 (CH), 125.9 (CH), 123.2 (C), 114.1 (2CH), 113.8 (2CH), 60.5 (CH), 55.5 (OCH₃), 55.3 (OCH₃), 42.8 (CH₂), 19.3 (CH₃).3-(2-Bromophenyl)-1-(4-methoxyphenyl)-3-(4-(3-methoxyphenyl)-2H-1,2,3-triazol-2-yl)propan-1-one (3c)Brown viscous liquid; yield: 62.0 mg (63%). ¹H NMR (400 MHz, CDCl₃): δ = 8.00 (d, J = 8.8 Hz, 2 H), 7.85 (s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.32–7.26 (m, 3 H), 7.22 (td, J = 0.8, 7.6 Hz, 1 H), 7.15 (td, J = 1.6, 7.6 Hz, 1 H), 6.95–6.92 (m, 4 H), 6.86 (dt, J = 2.4, 7.2 Hz, 1 H), 4.51 (dd, J = 10.8, 17.6 Hz, 1 H), 3.86 (s, OCH ₃, 3 H), 3.80 (s, OCH ₃, 3 H), 3.57 (dd, J = 3.2, 17.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 193.9 (CO), 163.7 (C), 159.8 (C), 147.6 (C), 139.2 (C), 133.2 (CH), 131.5 (C), 131.3 (CH), 130.5 (2CH), 129.7 (CH), 139.5 (CH), 129.3 (C), 128.0 (CH), 127.4 (CH), 122.0 (C), 118.4 (CH), 114.2 (CH), 113.7 (2CH), 111.1 (CH), 63.5 (CH), 55.4 (OCH₃), 55.2 (OCH₃).3-[4-(3-Fluorophenyl)-2H-1,2,3-triazol-2-yl]-1-(4-methoxyphenyl)-3-phenylpropan-1-one (3d)Pale-yellow solid; yield: 49.8 mg (62%); mp 136.0–137.0 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.00 (d, J = 8.8 Hz, 2 H), 7.82 (s, 1 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.45 (dd, J = 2.0, 10.0 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 2 H), 7.36–7.27 (m, 4 H), 6.99 (td, J = 2.4, 8.4 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 2 H), 6.51 (dd, J = 4.8, 9.2 Hz, 1 H), 4.51 (dd, J = 9.2, 17.6 Hz, 1 H), 3.86 (s, OCH ₃, 3 H), 3.67 (dd, J = 5.2, 17.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.2 (CO), 163.7 (C), 163.0 (d, J = 244.1 Hz, CF), 146.4 (C), 139.3 (C), 132.5 (d, J = 8.6 Hz, C), 131.1 (CH), 130.5 (2CH), 130.2 (d, J = 7.7 Hz, CH) 129.4 (C), 128.8 (2CH), 128.3 (CH), 126.6 (2CH), 121.5 (CH), 115.0 (d, J = 21.0 Hz, CH), 113.8 (2CH), 112.8 (d, J = 22.9 Hz, CH), 64.4 (CH), 55.4 (OCH₃), 43.5 (CH₂).3-[4-(3-Fluorophenyl)-2H-1,2,3-triazol-2-yl]-1-(4-methoxyphenyl)-3-(2-tolyl)propan-1-one (3e)Pale-yellow solid; yield: 5.7 mg (61%); mp 144.0–145.0 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.8 Hz, 2 H), 7.81 (s, 1 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.44 (d, J = 9.6 Hz, 1 H), 7.33 (q, J = 7.6 Hz, 1 H), 7.23–7.14 (m, 4 H), 6.99 (td, J = 2.0, 8.4 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 2 H), 6.68 (dd, J = 4.4, 9.6 Hz, 1 H), 4.52 (dd, J = 9.6, 17.6 Hz, 1 H), 3.87 (s, OCH ₃, 3 H), 3.58 (dd, J = 4.4, 17.6 Hz, 1 H), 3.59 (s, CH ₃, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.4 (CO), 163.8 (C), 163.0 (d, J = 244.1 Hz, CF), 146.3 (C), 137.7 (C), 135.2 (C), 132.6 (d, J = 7.6 Hz, C), 131.0 (CH), 130.8 (CH), 130.5 (2CH), 130.2 (d, J = 8.6 Hz, CH), 129.4 (C), 128.1 (CH), 126.5 (CH), 125.8 (CH), 121.5 (d, J = 2.9 Hz, CH), 115.0 (d, J = 21.0 Hz, CH), 113.8 (2CH), 112.8 (d, J = 22.9 Hz, CH), 60.7 (CH), 55.5 (OCH₃), 42.7 (CH₂), 19.33 (CH₃).3-[4-(2,5-Dimethoxyphenyl)-2H-1,2,3-triazol-2-yl]-1-(4-methoxyphenyl)-3-(4-nitrophenyl)propan-1-one (3f)Yellow viscous liquid: yield: 59.6 mg (65%). ¹H NMR (400 MHz, CDCl₃): δ = 8.17 (d, J = 8.4 Hz, 2 H), 8.12 (s, 1 H), 8.01 (d, J = 7.6 Hz, 2 H), 7.59 (t, J = 8.0 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.48 (d, J = 7.2 Hz, 2 H), 7.47 (t, J = 7.6 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 1 H), 6.85 (dd, J = 3.2, 8.8 Hz, 1 H), 6.62 (dd, J = 6.4, 7.6 Hz, 1 H), 4.52 (dd, J = 8.0, 17.6 Hz, 1 H), 3.85 (s, OCH ₃, 3 H), 3.83 (dd, J = 6.0, 17.6 Hz, 1 H), 3.76 (s, OCH ₃, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.1 (CO), 153.6 (C), 151.0 (C), 147.6 (C), 146.5 (C), 144.6 (C), 136.0 (C), 135.1 (CH), 133.7 (CH), 128.7 (2CH), 128.1 (2CH), 127.8 (2CH), 124.0 (2CH), 119.4 (C), 114.9 (CH), 113.1 (CH), 112.4 (CH), 63.2 (CH), 55.9 (OCH₃), 55.7 (OCH₃), 43.8 (CH₂).3-(4-Chlorophenyl)-3-[4-(2-chlorophenyl)-2H-1,2,3-triazol-2-yl]-1-phenylpropan-1-one (3g)Pale-yellow solid; yield: 57.4 mg (68%); mp 84.0–86.0 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.15 (s, 1 H), 8.01 (d, J = 7.6 Hz, 2 H), 7.81 (dd, J = 2.4, 7.6 Hz, 1 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.44–7.41 (m, 1 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.29–7.22 (m, 2 H), 6.53 (dd, J = 5.6, 8.4 Hz, 1 H), 4.52 (dd, J = 8.4, 18.0 Hz, 1 H), 3.78 (dd, J = 5.6, 18.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.4 (CO), 144.9 (C), 137.6 (C), 136.1 (C), 134.3 (CH), 134.2 (C), 133.5 (CH), 131.9 (C), 130.3 (2CH), 129.3 (CH), 128.9 (2CH and C), 128.6 (2CH), 128.2 (2CH), 128.1 (2CH), 126.8 (CH), 63.5 (CH), 43.8 (CH₂). 3-[4-(4-Chlorophenyl)-2H-1,2,3-triazol-2-yl]-1-(4-methoxyphenyl)-3-(4-tolyl)propan-1-one (3h)White solid; yield: 54.4 mg (63%); mp 125.0–127.0 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.99 (d, J = 8.8 Hz, 2 H), 7.79 (s, 1 H), 7.66 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.30 (d, 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 8.8 Hz, 2 H), 6.46 (dd, J = 5.2, 9.2 Hz, 1 H), 4.49 (dd, J = 8.8, 17.6 Hz, 1 H), 3.86 (s, OCH ₃, 3 H), 3.67 (dd, J = 5.2, 17.6 Hz, 1 H), 2.31 (s, CH ₃, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.3 (CO), 163.7 (C), 146.4 (C), 138.1 (C), 136.4 (C), 133.9 (C), 130.9 (CH), 130.5 (2CH), 129.4 (2CH), 129.4 (C), 129.0 (C), 128.8 (2CH), 127.1 (2CH), 126.6 (2CH), 113.7 (2CH), 64.2 (CH), 55.4 (OCH₃), 43.5 (CH₂), 21.1 (CH₃).3-[4-(3,4-Dimethoxyphenyl)-2H-1,2,3-triazol-2-yl]-3-(4-methoxyphenyl)-1-phenylpropan-1-one (3i)Yellow viscous liquid: yield: 54.1 mg (61%). ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 7.6 Hz, 2 H), 7.76 (s, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.35 (d, 8.8 Hz, 2 H), 7.25 (td, J = 1.6, 6.0 Hz, 2 H), 6.87–6.84 (m, 3 H), 6.45 (dd, J = 5.2, 8.8 Hz, 1 H), 4.51 (dd, J = 8.8, 17.6 Hz, 1 H), 3.86 (s, OCH ₃, 3 H), 3.86 (s, OCH ₃, 3 H), 3.74 (s, CH ₃, 3 H), 3.70 (dd, J = 5.2, 17.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.9 (CO), 159.3 (C), 149.0 (C), 147.3 (C), 136.3 (C), 133.2 (CH), 131.4 (C), 130.5 (CH), 128.5 (CH), 128.0 (2CH), 128.0 (C, merged with two CH), 127.8 (2CH), 123.2 (C), 118.3 (CH), 114.0 (2CH), 111.0 (CH), 109.0 (2CH), 63.6 (CH), 55.7 (2OCH₃), 55.1 (OCH₃) 43.9 (CH₂).3-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-[4-(4-methoxyphenyl)-2H-1,2,3-triazol-2-yl]propan-1-one (3j)White solid; yield: 57.3 mg (64%); mp 120.0–122.0 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.97 (d, J = 8.8 Hz, 2 H), 7.74 (s, 1 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.33 (q, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 6.91 (dd, J = 6.4, 8.4 Hz, 4 H), 6.45 (dd, J = 5.6, 8.4 Hz, 1 H), 4.40 (dd, J = 8.4, 17.6 Hz, 1 H), 3.85 (s, OCH ₃, 3 H), 3.81 (s, OCH ₃, 3 H), 3.70 (dd, J = 5.6, 17.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.1 (CO), 163.8 (C), 159.7 (C), 147.6 (C), 138.1 (C), 134.0 (C), 130.6 (CH), 130.5 (2CH), 129.3 (C), 128.9 (2CH), 128.2 (2CH), 127.2 (2CH), 122.9 (C), 114.1 (2CH), 113.8 (2CH), 63.5 (CH), 55.5 (2OCH₃), 55.3 (OCH₃), 43.5 (CH₂).